DESCRIPTION: The overall goal of this research proposal is to test the hypothesis that stable gamma-globin inducers which do not inhibit erythroid cell proliferation and may be given frequently, will result in superior long-term hemoglobin F inducibility in the absence of hematologic suppression in vivo. Specific aims are to: 1) identify oral fetal globin gene inducers with favorable in vivo kinetics; 2) determine the effects of long term administration of oral hemoglobin F inducers in non-human primates; and 3) determine whether synergy results with their combined use with other compounds known to stimulate HbF production. The primary screen for gamma-globin inducibility will be performed using K562 cells alone and those stably transfected with promoter/reporter constructs, erythroid progenitor cultures and a responsive multi-lineage cell line. Hemoglobin F inducers which stimulate or do not inhibit erythropoiesis in vitro will be studied in baboons to determine oral pharmacokinetics, safety and to develop effective long-term regimens.